Simvastatin interferes with process outgrowth and branching of oligodendrocytes

Abstract

Statins have attracted interest as a treatment option for multiple sclerosis (MS) because of their pleiotropic antiinflammatory and immunomodulatory effects. However, contradictory results have been described when they are applied to oligodendrocytes (OLGs), the cell type predominantly affected in MS. In this study we focus on the in vitro effect of statins on process outgrowth in OLN-93 cells, a well-characterized OLG-derived cell line, and primary cultures of neonatal rat OLGs. Application of the lipophilic simvastatin, as low as 0.1-1 μM, disturbs process formation of both cell types, leading to less ramified cells. We show that both protein isoprenylation and cholesterol synthesis are required for the normal differentiation of OLGs. It is further demonstrated that the expression of 2',3'-cyclic-nucleotide-3' phosphodiesterase (CNP) and tubulin is lowered, concomitant with a reduction of membrane-bound CNP as well as tubulin. Therefore, we propose that lack of isoprenylation of CNP could help to explain the altered morphological and biochemical differentiation state of treated OLGs. Moreover, expression of specific myelin markers, such as myelin basic protein, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein, was compromised after treatment. We conclude that simvastatin treatment has detrimental effects on OLG process outgrowth, the prior step in (re)myelination, thereby mortgaging long-term healing of MS lesions.

Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders

“…As for isoprenylation processes, both in vitro and in vivo results suggest that statin- and cell type play pivotal roles in the final outcome. Simvastatin treatment had a detrimental effect on oligodentrocyte outgrowth, a key step in the re(myelination) process [28], particularly in the early myelination stage [29] (Figure 1). Interestingly, simvastatin and lovastatin had an opposite effect on the myelin basic protein (MBP), since simvastatin treatment greatly increased the densities of MBP in oligodentrocytes of neonatal rats after hypoxia-ischemia damage [30], whereas lovastatin reduced MBP expression in primary oligodentrocytes, probably by impairment of the isoprenylation process [31] (Figure 1).…”

Regarding long-term statin therapy: Are we trading stronger hearts for weaker brains?

“…Central nervous system myelination requires extraordinary high levels of lipid synthesis and uptake of extracellular lipids [43] and statin therapy might impair myelination by blocking progenitor cell differentiation into myelin producing oligodendrocytes [44]. Moreover, the pleiotropic effects statins interfere with myelin formation in mature oligodendrocytes by altering Ras and Rho signaling [45][46][47]. It is disturbing that in a small 1-year pilot study, atorvastatin 80 mg daily compared to placebo resulted in a significant reduction in right hippocampal volume assessed by MRI [51].…”

“…In addition to the possible promotion of CAA resulting in impaired small vessel wall integrity, statin therapy impairs myelination in the brain [43][44][45][46][47]. The human brain is about 2% of the total body weight but contains 25% of total body cholesterol [48].…”

Regulation of Oligodendrocyte Differentiation: Relevance for Remyelination

“…Consequently, CNP is essential for OLG arborization and membrane expansion during myelination. Although cytoplasmic, CNP is anchored to the plasma membrane by isoprenylation and inhibition of CNP isoprenylation perturbs arborization and OLG differentiation Smolders et al, 2010). Similar to CNP, MBP can interact with both actin filaments and microtubules and is important for cytoskeleton integrity in OLG.…”